Biology subjects

Chiou, K. L.

Publications and source records attributed to Chiou, K. L..

13 recordsLinked to original sources

bioRxiv2025

Single-cell, multi-region profiling of the macaque brain across the lifespan

Brain aging is a complex process with profound health and societal consequences. However, the molecular and cellular pathways that govern its temporal progression-along with any cell type-, region-, and sex-specific heterogeneity in such progression-remain poorly defined. Here, we present a transcriptomic atlas of 5.3 million cells from 582 samples spanning 11 brain regions of 55 rhesus macaques (29 female, 26 male), aged 5 months (early life) to 21 years (late adulthood). We annotate 12 major cell classes and 225 subclusters, including region-specific subtypes of excitatory and inhibitory neurons, astrocytes, and ependymal cells. We identify a vulnerable excitatory neuron population in the superficial cortical lamina and a cortical interneuron population that are less abundant later in life, along with subtle, region-specific, age-associated compositional differences in subpopulations of microglia and oligodendrocytes, whose detection required single-cell resolution. Finally, we chart convergent and divergent age-associated molecular signatures across brain regions and cell classes-where some of these signatures are sex-specific and could underlie sex biases in neurological disorders. We find that age-associated transcriptional programs not only overlap substantially with those seen in Alzheimers disease (AD), but also unfold along distinct temporal trajectories across brain regions, suggesting that aging and AD may share molecular roots that emerge at different life stages and in region-specific, sex-specific windows of vulnerability. This work provides a temporal, regional, and sex-stratified atlas of the aging primate brain, offering insights into cell type-specific vulnerabilities and regional heterogeneity with translational human relevance.

neuroscience↗

bioRxiv2025

Disparate social structures are underpinned by distinct social rules across a primate radiation

Over six decades of research on wild baboons and their close relatives (collectively, the African papionins) have uncovered substantial variation in their behavior and social systems. While most papionins form discrete social groups (single-level societies), a few others form small social units that are nested within larger supergroups (multi-level societies). These two systems are generally thought to be qualitatively distinct, but data from wild populations increasingly suggest that there may be areas of overlap. To quantify this potential gradient in social structure, a more systematic, comparative analysis is needed. Here, we constructed a database of behavioral and demographic records spanning 135 group-years, 28 social groups, 13 long-term field studies, and 11 species to quantify variation in grooming network structure, and identify the individual and dyadic properties (e.g., kinship and social status effects) that underlie this variation. Consistent with accumulating observations in the field, the single-level species could be divided into two categories: cohesive and cliquish. Cohesive single-level networks were dense, kin-biased, and moderately rank-structured, while cliquish single-level networks were more differentiated, slightly more kin-biased, and strongly rank-structured. As expected, multi-level networks were very modular and shaped by females ties to specific dominant males but varied in their kin biases. Taken together, these data suggest that (i) kin and rank biases are widespread but vary in their strength; (ii) male-centered subgroups are exclusive to multi-level systems; and (iii) increases in network modularity can emerge in response to heightened nepotism and male-centered clustering. SIGNIFICANCE STATEMENTWhat forces explain variation in primate societies? While kinship and dominance shape the social lives of many of our close relatives, it is unclear how their effects differ across species. Using a new database comprising decades of field research, we found that baboons and their close relatives fell into three general patterns: one in which groups were cohesive, kin-biased, and moderately rank-biased, another in which groups were more cliquish and nepotistic, and a third in which groups were divided into clusters centered on dominant males. Distinct primate societies may thus reflect differences in the strength of females nepotistic biases and the degree of males social influence.

animal behavior and cognition↗

bioRxiv2025

Age and early life adversity shape heterogeneity of the epigenome across tissues in macaques

Age and early life adversity (ELA) are both key determinants of health, but whether they target similar physiological mechanisms across the body is unknown due to limited multi-tissue datasets from well-characterized cohorts. We generated DNA methylation (DNAm) profiles across 14 tissues in 237 semi-free ranging rhesus macaques, with records of naturally occurring ELA. We show that age-associated DNAm variation is predominantly tissue-dependent, yet tissue-specific epigenetic clocks reveal that the pace of epigenetic aging is relatively consistent within individuals. ELA effects on loci are adversity-dependent, but a given ELA has a coordinated impact across tissues. Finally, ELA targeted many of the same loci as age, but the direction of these effects varied, indicating that ELA does not uniformly contribute to accelerated age in the epigenome. ELA thus imprints a coordinated, tissue-spanning epigenetic signature that is both distinct from and intertwined with age-related change, advancing our understanding of how early environments sculpt the molecular foundations of aging and disease.

genomics↗

bioRxiv2023

Genome-wide coancestry reveals details of ancient and recent male-driven reticulation in baboons

Baboons (genus Papio) are a morphologically and behaviorally diverse clade of catarrhine monkeys that have experienced hybridization between phenotypically and genetically distinct phylogenetic species. We used high coverage whole genome sequences from 225 wild baboons representing 19 geographic localities to investigate population genomics and inter-species gene flow. Our analyses provide an expanded picture of evolutionary reticulation among species and reveal novel patterns of population structure within and among species, including differential admixture among conspecific populations. We describe the first example of a baboon population with a genetic composition that is derived from three distinct lineages. The results reveal processes, both ancient and recent, that produced the observed mismatch between phylogenetic relationships based on matrilineal, patrilineal, and biparental inheritance. We also identified several candidate genes that may contribute to species-specific phenotypes. One-Sentence SummaryGenomic data for 225 baboons reveal novel sites of inter-species gene flow and local effects due to differences in admixture.

evolutionary biology↗

bioRxiv2023

The biology of aging in a social world: insights from free-ranging rhesus macaques

Social adversity can increase the age-associated risk of disease and death, yet the biological mechanisms that link social adversities to aging remain poorly understood. Long-term naturalistic studies of nonhuman animals are crucial for integrating observations of social behavior throughout an individuals life with detailed anatomical, physiological, and molecular measurements. Here, we synthesize the body of research from one such naturalistic study system, Cayo Santiago Island, which is home to the worlds longest continuously monitored free-ranging population of rhesus macaques. We review recent studies of age-related variation in morphology, gene regulation, microbiome composition, and immune function. We also discuss ecological and social modifiers of age-markers in this population. In particular, we summarize how a major natural disaster, Hurricane Maria, affected rhesus macaque physiology and social structure and highlight the context-dependent and domain-specific nature of aging modifiers. Finally, we conclude by providing directions for future study, on Cayo Santiago and elsewhere, that will further our understanding of aging across different domains and how social adversity modifies aging processes.

immunology↗

bioRxiv2022

A generalizable epigenetic clock captures aging in two nonhuman primates.

Epigenetic clocks generated from DNA methylation array data provide important insights into biological aging, disease susceptibility, and mortality risk. However, these clocks cannot be applied to high-throughput, sequence-based datasets more commonly used to study nonhuman animals. Here, we built a generalizable epigenetic clock using genome-wide DNA methylation data from 493 free-ranging rhesus macaques. Using a sliding-window approach that maximizes generalizability across datasets and species, this model predicted age with high accuracy ({+/-} 1.42 years) in held-out test samples, as well as in two independent test sets: rhesus macaques from a captive population (n=43) and wild baboons in Kenya (n=271). Our model can also be used to generate insight into the factors hypothesized to alter epigenetic aging, including social status and exposure to traumatic events. Our results thus provide a flexible tool for predicting age in other populations and species and illustrate how connecting behavioral data with the epigenetic clock can uncover social influences on biological age.

evolutionary biology↗

bioRxiv2022

Evolutionary and biomedical implications of sex differences in the primate brain transcriptome

Humans exhibit sex differences in the prevalence of many neurodevelopmental and neurodegenerative conditions. To better understand the translatability of a critical nonhuman primate model, the rhesus macaque, we generated one of the largest multibrain region bulk transcriptional datasets for this species and characterized sex-biased gene expression patterns. We demonstrate that these patterns are similar to those in humans and are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate the rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and validate the rhesus macaque model for the study of these conditions.

neuroscience↗

bioRxiv2022

A single-cell multi-omic atlas spanning the adult rhesus macaque brain

Cataloging the diverse cellular architecture of the primate brain is crucial for understanding cognition, behavior and disease in humans. Here, we generated a brain-wide single-cell multimodal molecular atlas of the rhesus macaque brain. Altogether, we profiled 2.58M transcriptomes and 1.59M epigenomes from single nuclei sampled from 30 regions across the adult brain. Cell composition differed extensively across the brain, revealing cellular signatures of region-specific functions. We also identified 1.19M candidate regulatory elements, many novel, allowing us to explore the landscape of cis-regulatory grammar and neurological disease risk in a cell-type-specific manner. Together, this multi-omic atlas provides an open resource for investigating the evolution of the human brain and identifying novel targets for disease interventions.

neuroscience↗

bioRxiv2021

Subtype transcriptomic profiling of myeloid cells in Alzheimer Disease brain illustrates the diversity in active microglia phenotypes

Microglia contribute to Alzheimers Disease (AD) progression and are candidate therapeutic targets. Human microglia exhibit an array of transcriptional phenotypes implying that accurate manipulation of microglial function will require clarity of their molecular states and context dependent regulation. To increase the number of microglia analyzed per subject we employed fluorescence activated nuclei sorting prior to single-nucleus RNA-seq on human prefrontal cortices. We observed microglia phenotypes previously unrecognized in human brain gene expression studies and mapped their transcriptomic relationships by trajectory inference. Three clusters were enriched for endolysosomal pathways, one of which showed differential expression of AD GWAS genes in addition to genes implicated in nucleic acid detection and interferon signaling. Analysis of the "homeostatic" microglia cluster revealed a uniquely AD subcluster. Our study demonstrates the value of deeply profiling microglia to explore the biological implications of microglia transcriptomic diversity.

neuroscience↗

bioRxiv2021

High-altitude adaptation and incipient speciation in geladas

Survival at high altitude requires adapting to extreme conditions such as environmental hypoxia. To understand high-altitude adaptations in a primate, we assembled the genome of the gelada (Theropithecus gelada), an endemic Ethiopian monkey, and complemented it with population resequencing, hematological, and morphometric data. Unexpectedly, we identified a novel karyotype that may contribute to reproductive isolation between gelada populations. We also identified genomic elements including protein-coding sequences and gene families that exhibit accelerated changes in geladas and may contribute to high-altitude adaptation. Our findings lend insight into mechanisms of speciation and adaptation while providing promising avenues for functional hypoxia research.

genomics↗

bioRxiv2020

Rhesus macaques as a tractable physiological model of human ageing

Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from shorter-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research due to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population.

genomics↗

bioRxiv2019

Genomic signatures of extreme body size divergence in baboons

Kinda and gray-footed chacma baboons occupy opposite extremes of the body size distribution in extant baboons (genus Papio). In order to detect signatures of natural selection in these two species, we genotyped 24,790 genome-wide autosomal SNPs from populations of Zambian baboons using double digest RADseq. We scanned the genome for evidence of selection by identifying regions with extreme differentiation between populations. We find evidence of selection on body size influencing multiple genes in one or both species, including FGF1, ATXN2, and PRKCE. We also find an enriched signal of selection associated with biological processes involved in multicellular organism growth and development, cell proliferation and cell growth, nutrient metabolism, and chondrocyte differentiation. Finally, we find that selection has impacted components of the CCKR signaling pathway, which regulates food intake and metabolism, and the JAK/STAT signaling pathway, which mediates the effect of cytokine signals on processes including epiphyseal chondrocyte proliferation essential for longitudinal bone growth. Our findings highlight promising avenues for future studies disentangling the genetic architecture of body size in primates including humans.

evolutionary biology↗

bioRxiv2019

Genome-wide ancestry and introgression in a Zambian baboon hybrid zone

Hybridization in nature offers unique insights into the process of natural selection in incipient species and their hybrids. In order to evaluate the patterns and targets of selection, we examine a recently discovered ba-boon hybrid zone in the Kafue River valley of Zambia, where Kinda baboons (Papio kindae) and gray-footed chacma baboons (P. ursinus griseipes) coexist with hybridization. We genotyped baboons at 14,962 variable genome-wide autosomal markers using double-digest RADseq. We compare ancestry patterns from this genome-wide dataset to previously reported ancestry from mitochondrial-DNA and Y-chromosome sources. We also fit a Bayesian genomic cline model to scan for genes with extreme patterns of introgression. We show that the Kinda baboon Y chromosome has penetrated the species boundary to a greater extent than either mitochondrial DNA or the autosomal chromosomes. We also find evidence for overall restricted introgression in the JAK/STAT signaling pathway. Echoing results in other species including humans, we find evidence for enhanced and/or directional introgression of immune-related genes or pathways including the toll-like receptor pathway, the blood coagulation pathway, and the LY96 gene. Finally we show enhanced introgression and excess chacma baboon ancestry in the sperm tail gene ODF2. Together, our results eluci-date the dynamics of introgressive hybridization in a primate system while highlighting genes and pathways under selection.

evolutionary biology↗